Prostate cancer is the second leading cause of cancer death in American men, behind only lung cancer. In 2012, it is estimated that about 241,740 new cases of prostate cancer will be diagnosed and about 28,170 men will die of prostate cancer. Treatment options currently available for prostate cancer patients include surgery, radiation, hormonal therapy and chemotherapy. In addition, patients with castration-resistant prostate cancer with bone metastases are often treated with bisphosphonates to prevent skeletal-related events.
As a bone dominant disease, changes in prostate cancer metastases are difficult to assess using conventional imaging modalities, and only part of the treatment effect is reflected in serum prostate specific antigen (PSA) changes.
The need for molecular biomarkers predicting overall survival and monitoring treatment effects from a sample obtained repeatedly and with little inconvenience to the patient has recently focused on the technological advances in circulating tumor cell (CTC) detection, isolation, and capture. First described in 1869, CTC may be obtained from phlebotomy samples in a routine clinical practice setting. Initial studies of CTC in prostate cancer focused on detection of tumor cells using a reverse-transcription polymerase chain reaction (RT-PCR) based assay for the messenger RNA (mRNA) for PSA, also called kallikrein-related peptidase 3 (KLK3), in the mononuclear cell fraction of the blood that are presumed to be from CTC. To improve RT-PCR detection in peripheral blood, additional genes, highly expressed in tumor tissue and not expressed in peripheral blood nucleated cells (PBMC), have been studied as biomarkers to detect minimal residual or recurrent disease, such as prostate-specific membrane antigen, or markers of epithelial mesenchymal transition, or stem-cell origin. Depending on the sensitivity or specificity of the determinant being assayed, RT-PCR based detection rates range widely with disease extent in patients with castration resistant metastatic disease (CRPC). The wide range of results reflects the lack of standardization in sample processing and the analytical methods used for detection and in heterogeneous patient selection. Of particular interest, an early study using an RT-PCR based detection approach was the finding that PSA mRNA could be detected in patients who had no detectable serum PSA while responding clinically to androgen depletion therapy. This suggested that the continued detection of tumor cells in blood would provide unique clinical information relative to PSA because it represents an intrinsic property of the tumor that is independent of the level of androgens in the blood.
Before the role of any assay or device in medical decision-making can be determined, it is essential that it meet rigorous performance requirements. In particular, it is essential that the assay be “fit for the purpose” or “analytically valid” prior to evaluating the association of the biomarker(s) reported from using the assay with clinical outcomes. For the assay of CTC, it was not until the CellSearch assay was cleared by the Food and Drug Administration (FDA),19 that more extensive clinical CTC testing became feasible. With this assay, detection rates are highest in patients with advanced disease, and those who have progressed in multiple therapies. It followed that survival times varied inversely with baseline CTC number as a continuous variable, but survival times for patient with low counts ranged from very short to very long. The clinical utility of monitoring CTC changes with treatment as an efficacy-response surrogate biomarker of survival is currently being tested in large phase III trials.
A limitation of the assay was the failure to detect cells in a significant proportion of patients with CRPC for whom specific therapeutic approaches are being developed, particularly the pre-chemotherapy space, highlighting the need to develop assays that detect cells in more patients at a higher frequency.
Thus, there is a critical unmet need in prostate cancer drug development and treatment for outcome measures that reflect clinical benefit.